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Ritu Saini, MD NY Medical Skin Solutions New York University Langone Medical Center

Basal Cell Cancer: Update on Treatment and Management. Ritu Saini, MD NY Medical Skin Solutions New York University Langone Medical Center. Epidemiology. Most common cancer in humans Most common skin cancer Roughly 2,000,000 cases in the US annually 3:2 male to female ratio

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Ritu Saini, MD NY Medical Skin Solutions New York University Langone Medical Center

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  1. Basal Cell Cancer: Update on Treatment and Management Ritu Saini, MDNY Medical Skin SolutionsNew York University Langone Medical Center

  2. Epidemiology • Most common cancer in humans • Most common skin cancer • Roughly 2,000,000 cases in the US annually • 3:2 male to female ratio • Nonmelanoma skin cancers in the Medicare population went up an average of 4.2 percent every year between 1992 and 2006

  3. Risk Factors Syndromes- Basal cell nevus, XP, Bazex, Rombo

  4. Treatment • Mohs Surgery • Excisional Surgery • Currettage and Electrodessication • Cryosurgery • Laser Surgery • Radiation • Photodynamic Therapy • Topical chemotherapy

  5. Why pursue non-surgical treatment modalities • Patient not surgical candidate • Patient refuses surgical treatment • Lower costs?? • Cosmetically more acceptable • Reasonable cure rate

  6. Topical Chemotherapy

  7. Topical Chemotherapy • Imiquimod Immunomodulator • ↑ IFN-α, IL-6, TNF-α, natural killer cells, • ↑ nitric oxide secretion from macrophages • ↑ IFN- Gamma and antigen presentation • ↑ IL-12 and IL-18 via Toll-like Receptor 7 • Imiquimod stimulates both the innate and cell-mediated arms of the immune system.

  8. Imiquimod Indications • FDA approved Imiquimod 5% in 2004 for the treatment of superficial BCC (sBCC) in immunocompetent adults • Tumors > 0.5 cm 2 in area • < 2 cm in diameter located on trunk and extremities • 5 x’s/week for 6 weeks • What about nodular and morpheaform subtypes??

  9. Imiquimod • 41 patients with 47 tumors • 15 sBCC (including temple and forehead) • 26 nodular BCC (including nose, temple and canthus) • 6 sclerodermiform BCC (including nose and ear) • Protocol • Imiquimod 5% - 5 x’s/week for 6 weeks without occlusion • Additional punch biopsies from 22 tumors at treatment week 2 and week 6 • Follow up at three intervals up to 17 months for 39 patients Schiessl , C et al. J Drugs Dermatol. . 2007;6(5):507–513

  10. Imiquimod • Results • 95.7% complete response rate, 6.6% recurrence rate and 89.3% long-term clearance rate • Non-responding lesions belonged to nodular group on forehead • Histologic anaylsis of 22 tumor biopsies • 58% reduction of inflammatory infiltrate by from week 2 to week 6 • 72.7% clearance of tumor by week 2 (16 of 22 tumors) Schiessl , C et al. J Drugs Dermatol. . 2007;6(5):507–513

  11. Imiquimod • Side effects • Most common reactions were itching, burning and erosions equally divided • Mild • Moderate • Severe (all sclerodermiform- causing protocol changes) • Side effects healed with topical antibiotics • 14.9% scarring noted (not correlated with degree of side effect) Schiessl , C et al. J Drugs Dermatol. . 2007;6(5):507–513

  12. Imiquimod Schiessl , C et al. J Drugs Dermatol. . 2007;6(5):507–513

  13. Imiquimod • How do these findings compare?? • Prospective , multicenter phase 3, open-label study of 169 patients- sBCC • Protocol – Daily for 6 weeks • Initial clearance rate is 94.1% and • Sustained clearance rate by 60 months is 85.4% • Other studies report clearance rates from 75.0-80.8% 5x’s/week and 73.0-87.1% for daily usage. Quirk C et al. Cutis. 2010;85:318-324. Geisse J et al. J Am Acad Dermatol. 2004 May 50(5):722-733. Gollnick H et al. Eur J Dermatol. 2005 September;15(5):374-381.

  14. Pitfalls of Imiquimod • Can fail particularly if strict follow-up is not adhered to • How to determine if successful as clinical appearance may be misleading • Hypopigmentation and scarring can mask tumor • Ulceration from Imiquimod can mask tumor • 2/3 patients appearing clinically tumor free have residual BCC at biopsy site • Follow-up biopsies has been officially recommended by consensus groups • Efficacy based on compliance Murphy et al. Dermatol. Surg. 2008: 34: 1258-63

  15. Imiquimodvs Surgery • 5 year Clearance rates • Mohs Surgery • 0.7-6.5 % primary • 4-10% recurrent • Excisional Surgery • 1.2-10.1 % • Currettage and Electrodessication • 3.3-7.7 % Rowe DE J Dermatol Surg Oncol. 1989 March;15(3):315-328. Silverman MK et al . . J Dermatol Surg Oncol. 1991 September;17(9): 720-726. Silverman MK et al J Dermatol Surg Oncol. 1992 June;18(6):471-476 Werlinger KD et al Dermatol Surg. 2002 December;28(12):1138-1142.

  16. Imiquimod as Adjunctive Treatment • After Curettage and Electrodessication (C and E) • 20 patient study • Receive either imiquimod 5% or placebo after C and E for one month • Endpoint to reduced residual tumor one month after treatment (8 weeks) • 10% vs. 40% patients had residual tumor

  17. Imiquimod as Adjunctive Treatment • Before Mohs Surgery… • 31 patients with nasal nodular BCC • 16 patients received Mohs surgery alone • 15 patients received Mohs surgery after 4 weeks rest period following nightly application of Imiquimod 5% for 6 weeks Butler D, et al. Derm Surg 2009; 35 (1):24-9

  18. Imiquimod as Adjunctive Treatment

  19. Imiquimod as Adjunctive Treatment

  20. Is Imiquimod Cost-Effective? • Few studies comparing cost of Imiquimod to surgical excision • European Literature • Spanish Public health care system • Surgical excision of sBCC <2 cm with Imiquimod (5x’s/week for 6 weeks) for one year • € 676 vs € 621 • Treatment failures or cost to treat recurrences not addressed

  21. Is Imiquimod Cost-Effective? Netherlands study Norwegian Study • Imiquimod more cost-effective in short term • €585 vs surgery €663 • More expensive in the long run • €1471 vs surgery €1322 • Limitation is that there were no calculated estimated efficacies of Imiquimod • Imiquimod less cost-effective than standards of care (excision surgery, cryosurgery) • € 16 higher in imiquimod • More cost effective than PDT group • Better outcomes than cryosurgery at higher cost De cock E et al. Value in Health. 2005 November;8(6):A144. Sverre JM et al. Value in Health. 2005;8(6, article A143)

  22. Photodynamic Therapy

  23. Photodynamic Therapy (PDT) • Utilizes oxygen radicals generated from a photoactive molecule to achieve a therapeutic tissue response • Photoactivating light + Photosensitizer + Tissue Oxygen + Target Cell = Photochemical Reaction

  24. Photodynamic Therapy • Photosensitizers • Chemical Purity • Ability to target neoplastic tissue • Short interval between administration and peak accumulation in tumor • Short half-life • Rapid elimination from normal tissue • Ability to produce large amounts of cytotoxic products

  25. PDT-Topical Photosensitizers 5-delta-aminolevulinic acid HCL (ALA) Methyl-esterified ALA (mAL) • Metabolic precursor for endogenous photosensitizer protoporphyrin IX (Pp IX) • FDA approved for the treatment of AK’s in 1999 • More lipophilic and demonstrates deeper tissue penetration • FDA approved for the treatment of AK’s in 2004 NOT FDA approved for treatment of Basal Cell Carcinoma

  26. PDT-Topical Photosensitizers • Tumor thickness should not exceed 2-3 mm if using ALA • MAL is more suitable due to greater lipophilicity, greater selectivity, and better capacity for penetration • Currettage prior to PDT is indicated Szeimies RM Dermatol Clin. 2007;25:89-94.

  27. PDT- Light Sources • Broad spectrum lamps, diode lamps, and lasers • Light – emitting diodes (LED) • Pulsed Dye Lasers • Intense Pulsed Light • Maximum light absorption by porphyrins is close to 405 nm • Majority of studies use 625 to 633 nm permitting greater skin penetration (3 mm vs 0.75-1 mm) Kalka et al J Am Acad Dermatol. 2000;42:389-413; quiz 414-6.  

  28. PDT - Protocol • MAL-PDT (determined with ActiliteTm LED) • Lightly currette simply to debulk area (salicylic acid 3-5 % overnight if very crusted) • Apply MAL and allow to incubate under occlusion for 3 hours • Optional local anesthesia • 635 nm red light • Total dose of 37 J/cm2 (range 50-150 J/cm2) • Post-op care • 2 treatments, one week apart

  29. PDT - Efficacy • MAL-PDT and ALA-PDT • 76-97% clearance rates for sBCC • Haller et al treated 26 lesions twice one week apart with ALA-PDT 100% CR with one relapse 16 months post-PDT • Greater effectiveness if some type of debulking carried out prior • 64-92% for nodular BCC • Thissen et al treated 24 lesions with 92% CR • Soler et al treated 350 BCCs and curretted nodular lesions prior with 79% cure rate Haller JC et al. Br J Dermatol 2000;143:1270–5. Thissen MR et al Br J Dermatol 2000;142:338– Soler AM et al . Br J Dermatol 2001;145:467–71.

  30. PDT-Efficacy • Improves when photosensitizer injected intralesionally • For thicker skin cancers there are higher fluorescence levels and protoporphyrin IX levels after intralesional administration of 5-ALA as opposed to topical application • Therefore, enhanced efficacy and improved clearance rate Thissen MR et al. J Invest Dermatol 2002;118:239–45. De Blois AW et al. Lasers Med Sci 2002;17:208–15. Cappugi P et al. J Chemother. 2004 Oct;16(5):491-3.

  31. Pitfalls of PDT • Not FDA approved Limitations in studies especially in US literature • Penetration into skin not always adequate for bulkier tumors • Prolonged photosensitivity may be intolerable • Rare occurrences of skin cancer developing after PDT • Invasive SCC 4 months after three PDT treatment • Malignant Melanoma on scalp after multiple treatments • BCC on nose after one PDT treatment for biopsy proven actinic keratosis Varma S Br J Dermatol 2000;142:812–51 Wolf P Dermatology 1997;1:53–4 Karen J Dermatol Surg. 2010 Aug;36(8):1328-31 .

  32. PDT vs. Excision • MAL-PDT with red light- sBCC • Initial response rates similar • 51/52 (98%) lesions with surgery vs. 48/53 (91%) PDT • Long term – 12 months tumor free rates • 96% for surgery vs. 83% for MAL-PDT • MAL-PDT with red light- Nodular BCC • Similar findings for short term • 91% for MAL-PDT versus 98% for surgery • 5 –year clearance rate • 14% for MAL-PDT vs. 4% for surgery Rhodes LE et al. Arch Dermatol 2004;140:17–23. Tope WD et al. J Eur Acad Dermatol Venerol 2004;18 (Suppl 2):413–4.

  33. PDT vs. Imiquimod • MAL-PDT for sBCC • 13 patients with PDT vs. patients with Imiquimod • 7x’s day/week for three weeks over three months • One week between treatments • Clinical and histopathologic clearance rate at 3 months • 12/13 PDT group • 6/8 Imiquimod group Nikkels-Tassoudji N, et al. Acta Clin Belg 2005;60:227–34.

  34. PDT as Adjuvant Therapy • Case Report • 52 year old male with multifocal BCC on left shoulder • Treated with multiple surgical modalities 10 years prior • Biopsy showed recurrent BCC • Mohs surgery performed to 6 stages (12.5X9 cm) • More than 50% peripheral margin + for sBCC • MAL-PDT performed in lieu of continuing Mohs Reddy KK et al. J Drugs Dermatol. 2010 Feb;9(2):143-8

  35. PDT as Adjuvant Therapy • MAL-PDT after 3 hours of occlusion • 37 J/cm2 for 10 minutes • Protocol repeated one week later • Clearance was clinically determined • Wound completely re-epithelialized at 4 wks • Patient please with cosmetic outcome (decreased scar formation compared to previous surgeries)

  36. Is PDT Cost-Effective? • Study of sBCC and Bowen’s Disease • 67 patients with 86 tumors (32 sBCC) • 34 treated with surgery, 24 with Imiquimod and 28 with MAL-PDT • Clearance Rates • 89.5% MAL-PDT, 87.5% Imiquimod, and 97.5% surgery • Cost • Euros 307 savings Imiquimod vs. Surgery • Euros 302 saving MAL-PDT vs. surgery

  37. Summary • While surgery is clearly the gold standard, Imiquimod and photodynamic therapy clearly have a role in the treatment of basal cell carcinoma, especially superficial BCC • Utility as either primary or adjunctive treatment • Larger, prospective, randomized controlled-clinical trials are necessary to further determine the efficacy and cost-effectiveness of these treatments

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